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MFSD8 – Neuronal Ceroid Lipofuscinosis 7

Biallelic loss-of-function variants in MFSD8 cause autosomal recessive neuronal ceroid lipofuscinosis 7 (CLN7) (MONDO_0012588). Two unrelated human patients harbored pathogenic MFSD8 variants, including a compound heterozygous two-nucleotide deletion c.136_137del (p.Met46ValfsTer22) (PMID:35154277) and a homozygous whole-gene deletion confirmed by CNV-seq and qPCR (PMID:35917699). Clinically, affected individuals presented with seizures, aggressive behavior, ataxia, sleep disturbances, and rhabdomyolysis in the context of sepsis. A domestic shorthair cat with a homozygous frameshift in MFSD8 exhibited abnormal posture and diffuse brain dysfunction, supporting a conserved role in neurodegeneration.

Functional experiments demonstrate that CLN7 is a polytopic lysosomal membrane protein requiring an N-terminal dileucine motif for correct lysosomal targeting; missense mutations (e.g., p.Thr294Lys, p.Pro412Leu) enhance proteolytic cleavage and mislocalize CLN7 to the plasma membrane (PMID:20406422). In Cln7 knockout mouse embryonic fibroblasts, quantitative proteomics revealed depletion of soluble lysosomal proteins (including CLN5) and impaired mTORC1 reactivation under starvation, indicating a loss-of-function mechanism for CLN7 disease (PMID:29514215). These data provide limited genetic evidence with strong concordant functional data linking MFSD8 deficiency to CLN7 pathogenesis. Further natural history and segregation studies are needed to move beyond the current evidence cap.

Key Take-home: MFSD8 loss-of-function variants are a limited but emerging cause of autosomal recessive CLN7, with supportive functional and animal-model data underpinning diagnostic and research applications.

References

  • Frontiers in genetics • 2022 • Case Report: Novel MFSD8 Variants in a Chinese Family With Neuronal Ceroid Lipofuscinoses 7 PMID:35154277
  • Clinical neurology and neurosurgery • 2022 • Severe rhabdomyolysis in neuronal ceroid lipofuscinosis type 7 PMID:35917699
  • Traffic (Copenhagen, Denmark) • 2010 • Lysosomal targeting of the CLN7 membrane glycoprotein and transport via the plasma membrane require a dileucine motif. PMID:20406422
  • Human molecular genetics • 2018 • Loss of CLN7 results in depletion of soluble lysosomal proteins and impaired mTOR reactivation. PMID:29514215

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

2 unrelated probands with biallelic MFSD8 frameshift and deletion variants and supportive animal model data

Genetic Evidence

Limited

2 human probands with confirmed biallelic LoF MFSD8 variants ([PMID:35154277],[PMID:35917699])

Functional Evidence

Moderate

Mutational analyses show disrupted lysosomal targeting and enhanced proteolytic cleavage of CLN7 ([PMID:20406422]); Cln7 knockout MEFs exhibit lysosomal protein depletion and impaired mTORC1 reactivation ([PMID:29514215])